This project proposes a collaboration between Dr. Colleen Hadigan, Intramural Investigator at NIAID, and Dr. Steven Grinspoon, Professor of Medicine at MGH, to assess a novel strategy to reduce liver fat and improve liver histology in the large number of HIV patients with NAFLD and NASH. Liver disease is one of the most significant chronic co-morbid conditions among HIV patients, and, in the era of antiretroviral therapy, mortality from liver disease is second only to AIDS related mortality. An increasing percentage of HIV-infected patients (30-40%) are thought to have non-alcoholic fatty liver disease (NAFLD), characterized by triglyceride accumulation in hepatocytes that may progress to hepatic inflammation and significant hepatocellular injury. To date, therapies to treat NAFLD in HIV have been poorly studied. Investigation of new therapies is particularly urgent in HIV, in which contributors to NAFLD may be distinct from those in the general population. The current application will investigate a novel strategy to treat NAFLD in HIV using tesamorelin, a growth hormone releasing hormone (GHRH) analogue, which will address two potentially critical contributors to liver fat in HIV, namely increased visceral adiposity and increased hepatic de novo lipogenesis. Growth hormone is generally decreased in HIV-infected individuals with increased visceral adiposity. Tesamorelin, which increases endogenous growth hormone secretion, is an FDA approved therapy to reduce visceral fat in this population. Our current application builds on strong preliminary data, showing that tesamorelin reduced liver fat by 40% in association with reductions in visceral fat in a cohort chosen for visceral obesity. In the proposed studies, we will assess the efficacy of tesamorelin to reduce liver fat in patients chosen for NAFLD and increased transaminases, with the latter indicating inflammation and/or hepatocellular damage. We will also investigate effects of GHRH analogue on liver inflammation, hepatocellular damage, and liver fibrosis. We hypothesize that tesamorelin will reduce liver fat and also reduce hepatic inflammation and potentially hepatocellular injury. Further, to elucidate metabolic correlates of NAFLD, we will assess the effects of tesamorelin on hepatic de novo lipogenesis, and the effects of liver fat reduction on hepatic and whole body insulin sensitivity. In this U01 grant application, we will leverage a strong collaboration between experts in HIV-associated liver disease at NIAID, including Drs. Colleen Hadigan and Caryn Morse and David Kleiner, with a well-characterized clinical cohort with NAFLD and significant expertise in liver histology and Dr. Grinspoon and his team at MGH, who have worked to develop a successful strategy to reduce VAT in HIV patients. This application builds on preliminary data from both groups demonstrating the linkage between NAFLD and liver inflammation in HIV and the robust and novel effects of tesamorelin to reduce hepatic fat in this population. The proposed investigation will provide insight into the mechanism of this process in HIV patients and may suggest the first successful treatment for hepatic steatosis and inflammation in HIV patients.